Many bioactive agents including pharmaceuticals, nutrients, vitamins and so forth have a “functional window”. That is to say that there is a range of concentrations over which these agents can be observed to provide some biological effect. Where the concentration in the appropriate part of the body (e.g. locally or as demonstrated by serum concentration) falls below a certain level, no beneficial effect can be attributed to the agent. Similarly, there is generally an upper concentration level above which no further benefit is derived by increasing the concentration. In some cases increasing the concentration above a particular level results in undesirable or even dangerous effects.
Some bioactive agents have a long biological half-life and/or a wide functional window and thus may be administered occasionally, maintaining a functional biological concentration over a substantial period of time (e.g. 6 hours to several days). In other cases the rate of clearance is high and/or the functional window is narrow and thus to maintain a biological concentration within this window regular (or even continuous) doses of a small amount are required. This can be particularly difficult where non-oral routes of administration (e.g. parenteral administration) are desirable. Furthermore, in some circumstances, such as in the fitting of implants (e.g. joint replacements or oral implants) the area of desired action may not remain accessible for repeated administration. In such cases a single administration must provide active agent at a therapeutic level over the whole period during which activity is needed.
Sustained activity is furthermore important in situations where a physical soothing or barrier property is provided by a formulation. In such circumstances the biological effect may be provided by, for example, the separation of a biological tissue from some undesirable agent or environment or by the provision of a soothing interface between the tissue and its surroundings. Where compositions provide such a barrier or interfacial property, whether including a “drug” type active agent or not, it is an advantage if the composition is sufficiently permanent to allow a reasonable period between administrations.
Different methods have been used and proposed for the sustained release of biologically active agents. Such methods include slow-release, orally administered compositions, such as coated tablets, formulations designed for gradual absorption, such as transdermal patches, and slow-release implants such as “sticks” implanted under the skin.
One method by which the gradual release of a bioactive agent has been proposed is a so-called “depot” injection. In this method, a bioactive agent is formulated with carriers providing a gradual release of active agent over a period of a number of hours, days, weeks, or even months. These are often based upon a degrading matrix which gradually degrades and/or disperses in the body to release the active agent.
The most common of the established methods of depot injection relies upon a polymeric depot system. This is typically a biodegradable polymer such as poly (lactic acid) (PLA) and/or poly (lactic-co-glycolic acid) (PLGA) and may be in the form of a solution in an organic solvent, a pre-polymer mixed with an initiator, encapsulated polymer particles or polymer microspheres. The polymer or polymer particles entrap the active agent and are gradually degraded releasing the agent by slow diffusion and/or as the matrix is absorbed. Examples of such systems include those described in U.S. Pat. No. 4,938,763, U.S. Pat. No. 5,480,656 and U.S. Pat. No. 6,113,943 and can result in delivery of active agents over a period of up to several months. These systems do, however, have a number of limitations including the complexity of manufacturing and difficulty in sterilising (especially the microspheres). The local irritation caused by the lactic and/or glycolic acid which is released at the injection site is also a noticeable drawback. There is also often quite a complex procedure to prepare the injection dose from the powder precursor requiring reconstitution of the system before administration to a subject e.g. by injection.
From a drug delivery point of view, polymer depot compositions also have the disadvantage of accepting only relatively low drug loads and having a “burst/lag” release profile. The nature of the polymeric matrix, especially when applied as a solution or pre-polymer, causes an initial burst of drug release when the composition is first administered. This is followed by a period of low release, while the degradation of the matrix begins, followed finally by an increase in the release rate to the desired sustained profile. This burst/lag release profile can cause the in vivo concentration of active agent to burst above the functional window immediately following administration, then drop back through the bottom of the functional window during the lag period before reaching a sustained functional concentration. Evidently, from a functional and toxicological point of view this burst/lag release profile is undesirable and could be dangerous. It may also limit the equilibrium concentration which can be provided due to the danger of adverse effects at the “peak” point.
Previous depot systems have been sought to address the problem of burst release. In particular, the use of hydrolysed polylactic acid and the inclusion of poly lactic acid-polyethylene glycol block copolymers have been proposed to provide the “low burst” polymeric system described in U.S. Pat. No. 6,113,943 and U.S. Pat. No. 6,630,115. These systems provide improved profiles but the burst/lag effect remains and they do not address other issues such as the irritation caused by the use of polymers producing acidic degradation products.
One alternative to the more established, polymer based, depot systems is to use a lipid-based slow release matrix comprising a liquid crystalline phase. Systems of this type have been proposed, for example, in U.S. Pat. No. 5,151,272, and WO2005/117830. Such compositions have many advantages and are potentially highly effective, but in some situations it can be an advantage to have lipid based compositions that are even longer lasting, more resistant to chemical and/or enzymatic degradation and/or more physically robust than those proposed in the known literature.
The formation of non-lamellar phases in certain regions of the amphiphile (e.g. lipid)/water, amphiphile/oil and amphiphile/oil/water phase diagrams is a well known phenomenon. Such phases include non-lamellar liquid crystalline phases such as the cubic P, cubic D, cubic G, cubic micellar and hexagonal phases, which are fluid at the molecular level but show significant long-range order, and the L3 phase which comprises a multiply interconnected bi-continuous network of bilayer sheets which are non-lamellar but lack the long-range order of the liquid crystalline phases. Depending upon the mean curvature of the amphiphile sheets or layers, these phases may be described as normal (mean curvature towards the apolar region) or reversed (mean curvature towards the polar region).
Knowledge of the spontaneous or preferred curvature of a particular component allows some degree of prediction as to which structures will be formed or formable by that amphiphile in aqueous mixtures. However, particularly where mixtures of amphiphiles is concerned, the exact nature of the phase structure and physical properties of the composition will depend greatly upon the specific interaction between the components with each other and/or with the solvent and other components of the mixtures.
The non-lamellar liquid crystalline and L3 phases formed by certain amphiphiles and mixtures thereof are thermodynamically stable systems. That is to say, they are not simply a meta-stable state that will separate and/or reform into layers, lamellar phases or the like, but are the stable thermodynamic form of the lipid/solvent mixture.
The early attempts to develop lipid depot formulations, as in, for example, U.S. Pat. No. 5,151,272 and U.S. Pat. No. 5,807,573, using liquid crystal phases could in some cases be effective in terms of delivery but their performance was less than ideal in other critical properties. In particular, cubic liquid crystalline phases are relatively viscous in nature. This makes application with a standard syringe difficult, and possibly painful to the patient, and makes sterilisation by filtration impossible because the composition cannot be passed through the necessary fine-pored membrane.
WO2005/117830, for example, provides an improved system which has low viscosity so as to improve the ease of manufacturing, handling and administration with a standard syringe, allow for sterile filtration and reduce the pain on injection to the patient. However, for long-term depot formulations and/or for formulations having protective or soothing properties (such as surface-coating formulations for use in, for example, per-oral applications), a crucial property is related to the robustness of the gel formed by the pre-formulation in the presence of e.g. aqueous body fluids towards chemical and/or mechanical degradation, e.g. erosion/fragmentation/dissolution by endogenous surface active agents (surfactants), lipid-degrading enzymes and/or physical break-up.
The present inventors have now established that providing a pre-formulation comprising particular amphiphilic components, a biologically tolerable solvent and optionally at least one bioactive agent, especially in a low viscosity phase such as molecular solution, gives a pre-formulation with greatly improved mechanical and/or chemical/enzymatic robustness. In addition, the pre-formulation maintains many or all of the advantages of previous lipid depot systems, i.e. it is easy to manufacture, may be sterile-filtered, it has low viscosity (allowing easy and less painful administration), allows a high level of bioactive agent to be incorporated (thus allowing a smaller amount of composition to be used) and/or forms a desired non-lamellar depot composition in vivo having a controllable “burst” or “non-burst” release profile. Advantages in terms of the protective and/or soothing nature of the compositions may also be maintained. The compositions are also formed from materials that are non-toxic, biotolerable and biodegradable.
Due to its improved resistance to degradation from erosion and/or fragmentation by physical and/or chemical means, the pre-formulation is especially suitable for the formation of depot compositions following parenteral administration for long-term drug delivery, e.g. several days to several months after parenteral administration. The compositions are also advantageous for non-parenteral (e.g. local or topical) administration to body cavities and/or surfaces of the body or elsewhere.
In particular, the compositions of the current invention are more resistant to chemical/biological degradation and their mechanical resistance is improved in comparison with existing lipid depot systems, while retaining the ability to spontaneously self-assemble in situ. When tested in degradative/fragmenting systems which cause turbidity upon breakup of the depot, the turbidity factor of the present formulations has been demonstrated as being a factor of ten lower than for the previous lipid based liquid crystal forming systems. This makes the compositions of the invention particularly effective in terms of the longevity of release. They are also well suited for application in areas with high erosion/degradation problems, for example per-oral application, or lower-GI-tract applications.
A lipid-based, slow-release composition is described in WO2006/131730 for GLP-1 and analogues thereof using lipid mixtures comprising phosphatidyl choline. This is a highly effective formulation, but the concentration of active agent which can be included in the formulation is limited by its solubility. Evidently, a higher concentration of active agent, together with improved mechanical and/or chemical/enzymatic robustness allows for the possibility of even longer duration depot products, products maintaining a higher systemic concentration, and products having a smaller injection volume, all of which factors are of considerable advantage under appropriate circumstances. It would thus be of considerable value to establish a way by which higher concentrations of active agents could be included in a lipid-based depot formulation.
The present inventors have now further established that by incorporating at least one polar solvent a pre-formulation may be generated addressing many of the shortfalls of known depot formulations, and which may be applied to provide an improved controlled release of peptide active agent. By use of specific components in carefully selected ratios, and in particular with a mixture of an alcohol and a polar solvent, a robust depot formulation can be generated having a combination of properties exceeding the performance of even the known lipid controlled-release compositions.